Neonatal inflammation via persistent TGF-β1 downregulation decreases GABA A R expression in basolateral amygdala leading to the imbalance of the local excitation-inhibition circuits and anxiety-like phenotype in adult mice

• Published in: Neurobiology of disease 2022-07, Vol.169, p.105745
• Main Authors: Zhong, Haiquan, Rong, Jing, Yang, Yang, Liang, Min, Li, Yingchun, Zhou, Rong
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Anxiety Disorders - metabolism; Anxiety Disorders - pathology; Basolateral Nuclear Complex - metabolism; Basolateral Nuclear Complex - pathology; Down-Regulation; gamma-Aminobutyric Acid - metabolism; Inflammation - chemically induced; Inflammation - metabolism; Lipopolysaccharides - metabolism; Lipopolysaccharides - toxicity; Mice; Phenotype; Receptors, GABA-A - metabolism; Transforming Growth Factor beta1 - metabolism
• ISSN: 1095-953X
• DOI: 10.1016/j.nbd.2022.105745

Neonatal inflammation can increase the risk of anxiety disorder in adulthood. The balance between glutamatergic excitatory and GABAergic inhibitory transmissions in the basolateral amygdala (BLA) plays a vital role in controlling anxiety state. Based on the reports that early-life inflammation had adverse effects on GABAergic system, the aim of this study was to investigate whether and how neonatal inflammation affects excitatory-inhibitory circuits in the BLA resulting in anxiety disorder. Neonatal mice received a daily subcutaneous injection of lipopolysaccharide (LPS, 50 μg/kg) or saline on postnatal days 3-5. LPS-treated mice developed anxiety behaviors accompanied by the hyperactivity of adrenal axis in adulthood. Electrophysiological study revealed the increase of postsynaptic neuronal excitability in the cortical-BLA excitatory synapses of LPS mice which could be recovered by bath-application of GABA R agonist suggesting the impairment of GABAergic system in LPS mice. Compared with controls, GABA Rα2 subunit expression and density of GABA-evoked current in BLA principal neurons were reduced in LPS mice. Additionally, neonatal LPS treatment resulted in the down-regulation of transforming growth factor-beta 1 (TGF-β1) expression and PKC signaling pathway in the adult BLA. The local TGF-β1 overexpression in the BLA improved GABA Rα2 expression via up-regulating the activity of PKC signaling, which corrected GABA R-mediated inhibition leading to the abolishment of anxiety-like change in adrenal axis regulation and behaviors in LPS mice. These data suggest the persistent TGF-β1deficit induces the down-regulation of GABA Rα2 expression and subsequent disruption of the excitation-inhibition balance in the BLA circuits, which is the important mechanisms of neonatal inflammation-induced anxiety disorder.